DESCRIPTION (Adapted from the Investigator's Abstract) The-long range goal of this program is to understand the cellular and molecular mechanisms by which experience and learning alter synaptic connections. The synaptic connections from the tactile sensory neurons that mediate the defensive withdrawal reflex of the marine snail Aplysia have provided a powerful, tractable and productive model system for the analysis of simple forms of learning and behavioral modification. We have recently identified a new form of synaptic plasticity, burst-dependent protection from synaptic depression, that allows these animals to remain attentive to stimuli that are important, but repetitive; these stimuli would otherwise be ignored due to habituation. Burst-dependent protection provides an effective switch that prevents the process of synaptic decrement that normally occurs when these neurons are repeatedly activated. Investigation of this mechanism revealed that synaptic decrement in these cells actually involves an active switching-off of individual synaptic sites rather than a "passive run-down" due to depletion of transmitter stores. These studies will analyze the cellular processes responsible for synaptic decrement and how this decrement is prevented through burst-dependent protection when a repetitive stimulus is more salient. The findings may be important for improving alertness and learning in non-novel environments, e.g. at work or in the classroom, and for maintaining synaptic function in clinical situations where synapses deteriorate. These sensory neuron synapses can also be strengthened through associative plasticity during classical conditioning that closely resembles conditioning in mammals. Our work has demonstrated that during this learning, relationships between stimuli or events are recognized by dually regulated proteins that function as molecular coincidence detectors. During conditioning, the enzyme adenylyl cyclase provides a molecular site of associative stimulus convergence that integrates two signals triggered by behavioral events: calcium influx and release of modulatory transmitter. We have found that a number of the integration properties of the adenylyl cyclase can account for characteristic features of the conditioning. When the adenylyl cyclase, which is also involved in learning in mammals, detects relationships between stimuli, it initiates strengthening of synaptic connections via the transient intracellular messenger cAMP. The formation of long-term memory involves the conversion of this transient signal to stable synaptic modifications, which is mediated by activation of immediate-early genes. Our molecular experiment will investigate how associated training with pairing of calcium influx and modulatory transmitter enhances induction of immediate-early genes.